Temperature-Dependent Immunity

Scientists show that mice housed at room temperature are less able to fight tumors.

By Abby Olena | November 18, 2013

Mice huddle for warmth.KATHLEEN KOKOLUS AND ELIZABETH REPASKYNational Research Council recommendations dictate that laboratory mice be housed at a constant temperature—between 20°C and 26°C—to reduce the need for frequent cage cleaning and to help ensure lab staff comfort. But though their body temperatures do not change, the temperature at which mice maintain homeostasis without expending energy to combat cold stress—their thermoneutral temperature—is closer to 30°C or 31°C. While most mice cope with mild cold stress fairly well, until now scientists had not explored the effects of being cold on mice with tumors.

Researchers from the Roswell Park Cancer Institute in Buffalo, New York, have shown that mice housed at their thermoneutral temperature show reduced tumor formation and metastasis mediated by the adaptive immune system. Their work was published today (November 18) in Proceedings of the National Academy of Sciences.

“It’s one of the things that’s under everybody’s nose, and nobody really thought about it much,” said Mark Dewhirst, a professor of radiation oncology and pathology at Duke University in North Carolina, who was not involved in the work. “Everybody thought that mice would be fine at room temperature, but nobody ever thought to look,” he continued. That the authors demonstrate “quite profound effects on antitumor immunity is really pretty remarkable,” Dewhirst added. “This is quite a tour de force.”

A team led by Elizabeth Repasky, a professor of immunology at Roswell Park, housed mice at either subthermoneutral temperature (ST)—22°C to 23°C—or thermoneutral temperature (TT), and then injected them with cells from four different tumor types. In all four models, the scientists found that mice formed tumors less quickly at the higher temperature. They also showed that tumors were less likely to metastasize in mice at TT. In a different mouse model, where tumors have been shown to form in response to a carcinogen, the scientists demonstrated that tumor formation was also delayed at TT.

The authors attributed the differences in growth to the antitumor adaptive immune response, as mice with compromised immune systems did not exhibit a temperature-dependent difference in tumor formation. They also saw a reduction in immunosuppressive cells and an increase in CD8+ lymphocytes and activated CD8+ T cells when mice were housed at TT. Mice with tumors were shown to have a preference for temperatures even higher than TT, spending most of their time in the warmest spot available—a 38°C chamber—when given the choice, suggesting that they might feel colder than mice without tumors, who chose a chamber at TT.

“We’re very excited about this because we know that people model all kinds of diseases in mice,” said Repasky. “Without paying attention to this big change in their metabolism—because they’re making more heat—I think we’re really undermining the ability of these models to be accurate.”

“It’s really remarkable in the sense that we all do our experiments at a temperature that doesn’t really give us the optimal conditions for evaluating immune responses to tumors,” said Suzanne Ostrand-Rosenberg, a professor of biological sciences and biochemistry at the University of Maryland, Baltimore County, who did not participate in the research. “It’s really a game changer,” she continued. “We may be missing a lot of effective immunotherapies because we’re simply not doing things under the conditions that optimize the activation of the immune system in mice.”

The paper “may provide some insight into why studies in animal models, particularly with immune drug development, may not always predict what happens in the clinic,” added Gregory Lesinski, an assistant professor in the division of medical oncology at Ohio State University, who was not involved in the work.

“I think it will be important in the future to dissect out the role of temperature in these other cell subsets,” he continued. “[The authors have] done a really nice job with the T cells, but we can certainly learn a lot more about other cell types relevant to cancer and immunology.”

And while most people are not constantly cold, “stress is stress,” said Repasky. “Different types of stress that are endured by people are actually mediated by the same sympathetic nerve pathway [by which] cold stress is mediated in mice.”

Repasky said her group may have stumbled onto “a pathway that is easily manipulated in mice by the thermostat, but [that] might have implications for why people who seem to be a lot more chronically stressed than others do more poorly in response to, not only their cancer risk, but also their overall outcome after therapy.”

Comments

Well, there are the optimal temperatures for evaluating immune responses to tumors, and then there is reality. Mice in Florida might live in their thermoneutral zone half their lives, but not mice in Minnesota. Plus, in real life, ambient temperature swings during the day. Has anyone looked to see if the artificially constant ambient temperature provided in any laboratory environment is itself stressful to a nervous system evolved for natural oscillations?

Speaking of temperature dependent immune issues, allergies to heat and cold and to changes in temperature are another kind of immune reaction to temperature.

I had cold uticaria for a brief period as a youth- I would break out in whole body hives upon jumping into a cold swimming pool or the ocean or even confronting cold morning air upon leaving a warm building. Today I only sometimes get mild asthmatic wheezing in cold air and break out around my hairline and scalp upon the onset of colder fall/winter temperatures.

There also exists cholinergic or heat urticaria, a form of chronic hives that is caused by an increase in body temperature.

We know that there are heat shock proteins and that enzymes are temperature dependent in their activities, so temperature dependent effects in the immune system should not be surprising.

This outdated paradigm remains: antibiotic resistance (a function of the innate immune system) is typically selected by the presence of the antibiotic.

No paradigm shift has occurred despite what is known about the link from physics to chemistry via thermal stress associated with nutrient stress during adaptations to the epigenetic "landscape" in species from microbes to man.

Alternative splicings link the epigenetic landscape to the physical landscape of DNA in organized genomes. They clearly show that the adaptations are nutrient-dependent and pheromone-controlled. However, the adaptations are typically attributed to thermal stress and mutations. For example, this misattribution occurs even in the context of exhibited resistance to rifampicin in E. coli that is clearly nutrient-dependent since a fitness advantage results within the context of a thermal stress/low glucose environment.

The molecular mechanisms of alternative splicings do not change. Nutrient stress is thermal stress and social stress is thermal stress, which is probably why why both nutrient stress and social stress are linked to cancer and its progression. We should probably link it to cancer treatment before running off half-cocked again as if we didn't know about differences in temperature-controlled growth characteristics in other organisms that link stress to their morphology and proliferation.

The moderator of the human-ethology yahoo group owned by the International Society for Human Ethology, blocked my post, which was merely a link to this article. I did not include anything except the link, but he blocked me due to my comment above. His reason for not posting to the group is "Relevance plus redundancy re human ethology re" This outdated paradigm remains...

The problem is his stated belief that: “Random mutations are the substrates upon which directional natural selection acts.” That theory has been taught for several decades despite the fact that it has never been supported by experimental evidence. Experimental evidence supporting biological facts now includes what is known about physics, chemistry, and the conserved molecular mechanisms that link the epigenetic landscape to the physical landscape of out DNA in organized genomes of species from microbes to man.

But there are now attempts to remove cause and effect from any context that might otherwise lead to conflicts with past representations of the mutation-driven evolution of organismal complexity. See, for example: "Scientists are exploring how organisms can evolve elaborate structures without Darwinian selection." -- Carl Zimmer

"Others maintain that as random mutations arise, complexity emerges as a side effect, even without natural selection to help it along. Complexity, they say, is not purely the result of millions of years of fine-tuning through natural selection—the process that Richard Dawkins famously dubbed “the blind watchmaker.” To some extent, it just happens."

If organismal complexity "just happens" there is less reason to teach physics, chemistry, or biology to students. Instead, they must simply learn to accept the explanation that organismal complexity, like cancer and other diseases and disorders, "just happens."

"...but nobody ever thought to look" is the statement of importance here.

Here are a few other things, out of a long possible list, that they "never thought to look" a:.

1) natural nutrition versus fastfoods.

2) constant ultrasounds, and other invasive procedures as per the human pregnancy "management". The problem there is that they can't mimic the psychological stress that the agressive medical model of pregnancy management imposes on a human mother, which - like infections, initiates a cytokine response which also affect the foetus.

3) serial vaccines within a time appropriate frame, to both mothers and baby mice, mimicking the phenomenal immune stress imposed on human neonates through maternal and neonatal activation of cytokine pathways, which should be in a constant anti-inflammatory phenotype - not being forced to regularly shift to a pro-inflammatory phenotype.

5) The effects on the mouse microbiome of replicating the current completely irresponsible atttitudes of the medical model in pregnancy and neonatal medicine of regularly napalming the body flora. We already know that the immune systems of germ-free baby mice, kept germ free until adulthood, do not return to normal when "conventionalised" with good flora. There is an immune system programming dependant upon that flora not being disturbed. The medical literature shows there is ONE window of opportunity to get it "right" and if you fail, then everything else falls apart too.

It's not just "poverty" and "disadvantage" which is the main driver. It's interesting how researchers constantly ignoring that the medical model now imposes a ridiculously high level of physiological stressors on mothers and neonates. That too is a stress which can shorten telomeres and cause non-infectious inflammatory epigenetic stress.

So there is another whole huge area that either "hasn't been thought of" or has been by-passed.

Who would want to look at the role the medical profession might play in creating problems? Particularly if really studying daily life stressors imposed by the medical model on mothers and babies in early life...., might have funding repercussions.

Why are scientists always assuming that the main stressors are to be found outside of themselves? And why are scientists always assuming that they would be easily fixed by themselves?

Start asking HUMAN mothers what the biggest stresses being placed in them and their children are, and the scientists will be forced to look at the three fingers pointing at them, while they point one finger at families and the environment.